Melanoma incidence and mortality have been rapidly increasing over the past fifty years, and the disease remains a public health burden. Although much research has been conducted in developing novel systemic treatments for melanoma, none have been very effective. With the molecular identification of cytotoxic T lymphocyte (CTL) responses to melanoma tumor antigens, many promising new trials are targeting the up-regulation of these responses in therapy for advanced melanomas. However, the natural history of the CTL anti-melanoma immune response in melanoma is not known. We propose to investigate the role of primary anti-melanoma immune responses in melanoma development. This cross-sectional study will examine the anti- melanoma CTL immune response across stage of disease, including patients with benign nevi, atypical nevi, and stage 0-IV melanomas. Ninety-eight cases will be enrolled with malignant melanoma diagnosed at the Mayo Clinic over a two-year time period. We will also ascertain 30 patients with a diagnosis of aytpical nevus and 30 patients with a benign nevus removed at the Mayo Clinic during this same time period and who have a similar age distribution as the cases. Participants will complete a structured self-administered questionnaire soliciting sun-exposure, medical and lifestyle history, and provide a blood sample for analyses. All melanoma cases and patients with benign and atypical nevi will undergo central pathology review. Furthermore, immune responses to the gp100, MART-1, and tyrosinase melanoma-specific peptides will be examined using tetramer, ELISPOT and RT-PCR techniques. The epidemiologic risk factor information will allow for adjustment of known melanoma risk factors in our primary analyses as well as investigating associations of these risk factors with anti- melanoma immune response. We have assembled an interdisciplinary research team for this study to create an outstanding research resource. In summary, we will characterize the role of primary anti-tumor CTL immune responses in melanoma development. This should greatly contribute to our understanding of the natural history and immunobiology of human melanoma, allowing for the development of rational immunotherapeutics.